2,6-dialkyl-4-(benzothiazol- or benzoxazol-4-yl-1,4-dihydropyridines

ABSTRACT

2,6-dialkyl-4-(benzothiazol- or benzoxazol-7-yl)-1,4-dihydropyridines which exhibit positive inotropic action with largely neutral vascular behavior, of the formula ##STR1## in which R 1  and R 5  are identical or different and represent straight-chain or branched alkyl having up to 8 carbon atoms, 
     R 2  represents nitro or cyano, or 
     R 1  and R 2  together form a lactone ring of the formula ##STR2## R 3  represents a radical of the formula ##STR3## R 4  -R 7  are defined hereinafter and physiologically acceptable salts thereof.

The invention relates to novel dihydropyridines substituted byheterocycles, processes for their preparation and their use inmedicaments, in particular in agents having positive inotropic action.

It is already known that 1,4-dihydropyridines have vasodilatingproperties and can be used as coronary agents and antihypertensives[compare Brit. Patent 1,173,062 and 1,358,951; DE-OS (German PublishedSpecification) 2,629,892 and 2,752,820]. Furthermore, it is known that1,4-dihydropyridines cause an inhibition of the contractility of smoothand cardiac muscles and can be employed for the treatment of coronaryand vascular disorders [compare Fleckenstein, Ann. Rev. Pharmacol.Toxicol., 17, 149-166 (1977)].

It is moreover known that, in addition to a positive inotropic cardiacaction, 3-nitro-dihydropyridines can in general have the disadvantage ofan undesired constricting action on the coronary vessels [compareSchramm et al., Nature 303, 535-537 (1983) and DE-OS (German PublishedSpecification) 3,447,169].

With knowledge of the prior art, it was unforeseeable that the compoundsaccording to the invention would have a positive inotropic action on theheart muscle, increasing the contractility and having largely neutralvascular behavior.

The invention relates to new dihydropyridines substituted byheterocycles, of the general formula (I) ##STR4## in which R¹ and R⁵ areidentical or different and represent straight-chain or branched alkylhaving up to 8 carbon atoms,

R² represents nitro or cyano, or

R¹ and R² together form a lactone ring of the formula ##STR5## R³represents a radical of the formula ##STR6## in which R⁶ denoteshydrogen, halogen or straight-chain or branched alkyl or alkoxy in eachcase having up to 8 carbon atoms, and

R⁷ denotes aryl having 6 to 10 carbon atoms, which is optionallymonosubstituted or disubstituted by identical or different substituentsfrom the series comprising halogen, nitro, cyano, trifluoromethyl,trifluoromethoxy, trifluoromethylthio, straight-chain or branched alkyl,alkoxy or alkoxycarbonyl in each case having up to 8 carbon atoms, andcarboxyl, or

denotes thienyl or pyridyl,

R⁴ represents hydrogen, or

represents straight-chain or branched alkyl, alkenyl, alkadienyl oralkynyl in each case having up to 10 carbon atoms which are optionallymonosubstituted or disubstituted by identical or different substituentsfrom the series comprising halogen, hydroxyl, carboxyl, cyano, nitro,phenoxy and straight-chain or branched alkylthio, alkoxy,alkoxycarbonyl, acyl or acyloxy in each case having up to 8 carbonatoms, and phenoxy or phenyl, it being possible for the latter in turnto be monosubstituted or disubstituted by identical or differentsubstituents from the series comprising halogen and straight-chain orbranched alkyl or alkoxy in each case having up to 6 carbon atoms,

and their physiologically acceptable salts.

Physiologically acceptable salts can be salts of the compounds accordingto the invention with inorganic or organic acids. Preferred salts arethose with inorganic acids such as, for example, hydrochloric acid,hydrobromic acid, phosphoric acid or sulphuric acid, or salts withorganic carboxylic or sulphonic acids such as, for example, acetic acid,maleic acid, fumaric acid, malic acid, citric acid, tartaric acid,lactic acid, benzoic acid, or methanesulphonic acid, ethanesulphonicacid, phenylsulphonic acid, toluenesulphonic acid ornaphthalenedisulphonic acid.

The compounds according to the invention exist in stereoisomeric formswhich either behave as image and mirror image (enantiomers) or which donot behave as image and mirror image (diastereomers). The inventionrelates both to the antipodes and the racemic forms as well as thediastereomer mixtures. The racemic forms, like the diastereomers, can beseparated into the stereoisomerically uniform components in a knownmanner (compare E. L. Eliel, Stereochemistry of Carbon Compounds, McGrawHill, 1962).

Preferred compounds of the general formula (I) are those

in which

R¹ and R⁵ are identical or different and represent straight-chain orbranched alkyl having up to 6 carbon atoms,

R² represents nitro or cyano, or

R¹ and R² together form a lactone ring of the formula ##STR7## R³represents a radical of the formula ##STR8## in which R⁶ denoteshydrogen, fluorine, chlorine or straight-chain or branched alkyl oralkoxy in each case having up to 2 carbon atoms, and

R⁷ denotes phenyl which is optionally substituted by fluorine, chlorine,nitro, cyano, trifluoromethyl or by straight-chain or branched alkyl oralkoxy in each case having up to 6 carbon atoms, or

denotes pyridyl or thienyl,

R⁴ represents hydrogen or

represents straight-chain or branched alkyl or alkenyl in each casehaving up to 8 carbon atoms which are optionally substituted byfluorine, chlorine, hydroxyl, carboxyl, cyano, nitro or bystraight-chain or branched alkylthio, alkoxy, alkoxycarbonyl, acyl oracyloxy in each case having

up to 6 carbon atoms or by phenoxy or phenyl, and their physiologicallyacceptable salts.

Particularly preferred compounds of the general formula (I) are those

in which

R¹ and R⁵ are identical or different and represent straight-chain orbranched alkyl having up to 4 carbon atoms,

R² represents nitro or cyano, or

R¹ and R² together form a lactone ring of the formula ##STR9## R³represents a radical of the formula ##STR10## in which R⁶ denoteshydrogen, chlorine or methyl,

R⁷ denotes phenyl which is optionally substituted by fluorine, chlorine,nitro, trifluoromethyl or straight-chain or branched alkyl, acyl oralkoxy in each case having up to 4 carbon atoms, or

denotes pyridyl

R⁴ represents hydrogen, or

represents straight-chain or branched alkyl having up to 6 carbon atoms,which is optionally substituted by hydroxyl, carboxyl, cyano or bystraight-chain or branched alkoxycarbonyl, alkoxy or acyloxy in eachcase having up to 4 carbon atoms,

and their physiologically acceptable salts.

A process for the preparation of the compounds of the general formula(I) according to the invention has additionally been found,characterized in that in the case in which R¹ and R² have theabovementioned meanings, but do not together form a lactone ring,

[A] compounds of the general formula (II)

    R.sup.3 --CHO                                              (II)

in which

R³ has the abovementioned meaning,

are first reacted with acetoacetic esters of the general formula (III)

    R.sup.5 --CO--CH.sub.2 --CO.sub.2 --R.sup.4                (III)

in which

R⁴ and R⁵ have the abovementioned meanings,

if desired with the isolation of the corresponding ylidene compounds ofthe general formula (IV) ##STR11## in which R³, R⁴ and R⁵ have theabovementioned meanings,

and then are reacted either with compounds of the formula (V)

    R.sup.1 --CO--CH.sub.2 --R.sup.2                           (V)

in which

R¹ and R² have the abovementioned meanings,

in inert solvents, in the presence of ammonia or ammonium salts,

or directly with enamino derivatives of the general formula (VI)##STR12## in which R¹ and R² have the abovementioned meanings,

or

[B] the aldehydes of the general formula (II) are first reacted with thecompounds of the general formula (V), if desired with the isolation ofthe ylidene compounds of the general formula (VII) ##STR13## in whichR¹, R² and R³ have the abovementioned meanings,

and in a next step reacted with the abovementioned compounds of thegeneral formula (III) in inert solvents, in the presence of ammonia orammonium salts or directly with enaminocarboxylic acid derivatives ofthe general formula (VIII) ##STR14## in which R⁴ and R⁵ have theabovementioned meanings,

or in the case in which R¹ and R² together form a lactone ring,

[C] first, according to those methods given under [A] and [B], compoundsof the general formula (Ia) ##STR15## in which R³, R⁴ and R⁵ have theabovementioned meanings,

R⁸ represents a C₁ -C₆ -alkyl radical and

R⁹ represents a leaving group such as, for example, chlorine or acetoxy,

are prepared and, according to known methods, an acid- or base-catalyzedring closure is added,

and in the case in which R⁴ does not denote hydrogen,

[D] compounds of the general formula (I), in which R¹, R², R³, R⁴ and R⁵have the abovementioned meanings and R⁴ represents hydrogen, are reactedwith the corresponding alcohols, if appropriate via a reactive acidderivative, in which case by use of the enantiomerically pure carboxylicacid the corresponding enantiomers of the ester are obtained.

The processes according to the invention can be illustrated by thefollowing equation: ##STR16##

Suitable solvents for processes [A], [B] and [C] are all inert organicsolvents. These preferably include alcohols such as methanol, ethanol,n- or iso-propanol, ethers such as diethyl ether, tetrahydrofuran,dioxane or glycol monoethyl ether or glycol diethyl ether, glacialacetic acid, pyridine, dimethylformamide, dimethyl sulphoxide,acetonitrile or hexamethylphosphoric triamide or toluene.

Suitable solvents for process [D] are the abovementioned solvents withthe exception of the alcohols.

The reaction temperature for the processes [A], [B], [C] and [D] can bevaried within a relatively wide range. In general, the reaction iscarried out in a range from 10° C. to 200° C., preferably from 20° C. to150° C.

The processes can be carried out at normal pressure, and at elevated orreduced pressure (for example from 0.5 to 5 bar), preferably at normalpressure.

When carrying out the processes according to the invention, any desiredratio of the substances participating in the reaction can be used. Ingeneral, however, molar amounts of the reactants are used.

Suitable reagents for the activation of the carboxylic acid are thecustomary reagents such as inorganic halides, for example thionylchloride, phosphorus trichloride or phosphorus pentachloride, orcarbonyldiimidazole, carbodiimides such as dicyclohexylcarbodiimide or1-cyclohexyl-3-[2-(N-methylmorpholino)ethyl]-carbodiimide-p-toluenesulphonateor N-hydroxyphthalimide or N-hydroxy-benzotriazole.

Enantiomerically pure forms are obtained, for example, by separatingmixtures of diastereomers of the compounds of the general formula (I),in which R⁴ represents an optical ester radical, by a customary method,then preparing the enantiomerically pure carboxylic acids and then, ifdesired, converting them into the enantiomerically pure dihydropyridinesby esterification with appropriate alcohols.

Chiral ester radicals which are suitable are all esters ofenantiomerically pure alcohols such as, for example, 2-butanol,1-phenylethanol, lactic acid, lactic acid esters, mandelic acid,mandelic acid esters, 2-aminoalcohols, sugar derivatives and many otherenantiomerically pure alcohols.

The diastereomers are in general separated either by fractionalcrystallization, by column chromatography or by Craig partition. Whichis the optimum process must be decided from case to case, and sometimesit is also expedient to use combinations of the individual processes.Separation by crystallization or Craig partition or a combination ofboth processes is particularly suitable.

The enantiomerically pure dihydropyridines are preferably esterified inethers such as diethyl ether or tetrahydrofuran, dimethylformamide,methylene chloride, chloroform, acetonitrile or toluene.

The aldehydes of the general formula (II) are also new and can beprepared by a process in which

a) either compounds of the general formula (IX)

    R.sup.31 --CH.sub.3                                        (IX)

in which

R^(3') represents the radicals of the formula ##STR17## in which R⁶ andR⁷ have the abovementioned meanings,

are halogenated to give compounds of the general formula (X)

    R.sup.3' --CH.sub.2 --Hal                                  (X)

in which

R^(3') has the abovementioned meaning and

Hal represents halogen, preferably bromine,

reacted with acetate ions and then hydrolyzed to give compounds of thegeneral formula (XI)

    R.sup.3' --CH.sub.2 OH                                     (XI)

in which

R^(3') has the abovementioned meaning,

and in a last step oxidized by a customary method,

b) or by a process in which compounds of the general formula (XII)

    R.sup.3" --CH.sub.3                                        (XII)

in which

R^(3") represents a radical of the formula ##STR18## in which R⁶ and R⁷have the abovementioned meanings,

are halogenated to give compounds of the general formula (XIII)

    R.sup.3" --CH(Br).sub.2                                    (XIII)

in which

R^(3") has the abovementioned meaning,

and then hydrolyzed by a customary method.

The process according to the invention can be illustrated by way ofexample by the following equation: ##STR19##

Suitable solvents in this case are all inert organic solvents which donot change under the reaction conditions. These preferably includealcohols such as methanol, ethanol, propanol or isopropanol, or etherssuch as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether,or diethylene glycol dimethyl ether or amides such ashexamethylphosphoric triamide or dimethylformamide, or acetic acid. Itis also possible to use mixtures of the solvents mentioned.

Suitable oxidizing agents in the case of the hydroxymethyl compoundsare, for example, manganese dioxide, dimethyl sulphoxide, ceric ammoniumnitrate, dipyridine-chromium(VI) oxide, sodium dichromate,iodosobenzene, pyridine chlorochromate, silver carbonate on celite orJones reagent. Manganese dioxide is preferred.

The oxidations and reductions can be carried out at normal pressure orat elevated or reduced pressure (for example from 0.5 to 5 bar),preferably at normal pressure.

The compounds of the general formula (IX) are known [compare Acta Chem.Second Ser B., 31, 203 (1977)].

The compounds of the general formula (X) are known or can be prepared bymethods known from the literature [compare J. Org. Chem. 46, 3259(1981)].

The acetoacetic esters of the formula (III) are known or can be preparedby customary methods [compare D. Borrmann, "Umsetzung von Diketonen mitAlkoholen, Phenolen und Mercaptanen" (Reaction of diketones withalcohols, phenols and mercaptans), in Houben-Weyl, Methoden derorganischen Chemie, (Methods of Organic Chemistry), Vol. VIII/4, 230 etseq. (1968)].

The ylidene compounds (IV) and (VII) are new, but can be prepared bycustomary methods [compare H. Dornow and W. Sassenberg, Liebigs Ann.Chem. 602, 14 (1957)].

The aminocrotonic acid derivatives of the formula (VI) and (VIII) areknown or can be prepared by known methods [S. A. Glickman, A. C. Cope,J. Am. Chem. Soc. 67, 1017 (1946)].

The compounds of the general formula (V) are also known [compare N.Levy, C. W. Scaife, J. Chem. Soc. (London) 1946, 1100; C. D. Hurd, M. E.Nilson, J. Org. Chem. 20, 927 (1955)].

The above preparation processes are only indicated for clarification.The preparation of the compounds of the formula (I) and (II) is notrestricted to these processes, but any modification of these processescan be used in the same way for the preparation of the compoundsaccording to the invention.

The compounds according to the invention exhibit an unforeseeable,valuable pharmacological action spectrum. They influence thecontractility of the heart and the tone of the smooth musculature. Theycan therefore be employed in medicaments for influencing pathologicallyaltered blood pressure, as coronary therapeutics and for the treatmentof cardiac insufficiency. Moreover, they can be used for the treatmentof cardiac arrhythmias, for the reduction of blood sugar, for thedetumescence of mucosal membranes and for influencing the salt and fluidbalance.

The cardiac and vascular effects were discovered in the isolatedperfused guinea-pig heart.

For this, the hearts of 250 to 350 g guinea-pigs are used. The animalsare sacrificed by a blow to the head, the thorax is opened and a metalcannula is tied into the exposed aorta. The heart is separated out ofthe thorax with the lungs and attached to the perfusion apparatus withcontinuous perfusion via an aortic cannula. The lungs are separated atthe lung roots. A KrebsHenseleit solution (1) (118.5 mmol/1 of NaCl,4.75 mmol/l of KCl, 1.19 mmol/l of KH₂ PO₄, 1.19 mmol/l of MgSO₄, 25mmol/l of NaHCO₃, 0.013 mmol/l of Na₂ EDTA) whose CaCl₂ content is 1.2mmol/l is used as the perfusion medium. 10 mmol/l of glucose are addedas an energy-producing substrate. The solution is filtered particle-freebefore the perfusion. The solution is aerated with carbogen (95% O₂, 5%CO₂) to maintain a pH of 7.4. The hearts are perfused with a constantflow (10 ml/min) at 32° C. by means of a peristaltic pump.

To measure the cardiac function, a liquid-filled latex balloon which isconnected to a pressure transducer via a liquid column is insertedthrough the left auricle into the left ventricle, and the isovolumetriccontractions are recorded on a rapid recorder (Opie, L., J. Physiol 180(1965), 529-541). The perfusion pressure is recorded by means of apressure transducer which is connected to the perfusion system upstreamof the heart. Under these conditions, a reduction in the perfusionpressure indicates a coronary dilatation, and an increase or decrease inthe left ventricular contraction amplitude indicates a reduction or anincrease in the heart contractility. The compounds according to theinvention are perfused into the perfusion system in suitable dilutionsshortly upstream of the isolated heart.

The new active compounds can be converted in a known manner into thecustomary formulations, such as tablets, coated tablets, pills,granules, aerosols, syrups, emulsions, suspensions and solutions, usinginert, non-toxic, pharmaceutically suitable excipients or solvents. Inthis connection, the therapeutically active compound should in each casebe present in a concentration of about 0.5 to 90% by weight of the totalmixture, i.e. in amounts which are sufficient in order to achieve thedosage range indicated.

The formulations are prepared, for example, by extending the activecompounds with solvents and/or excipients, if appropriate usingemulsifiers and/or dispersants, where, for example, in the case of theuse of water as a diluent, organic solvents can optionally be used asauxiliary solvents.

Administration is carried out in a customary manner, preferably orallyor parenterally, in particular perlingually or intravenously.

In general it has proved advantageous on intravenous administration toadminister amounts of about 0.001 to 1 mg/kg, preferably about 0.01 to0.5 mg/kg of body weight to achieve effective results, and on oraladministration the dosage is about 0.01 to 20 mg/kg, preferably 0.1 to10 mg/kg of body weight.

In spite of this, it may be necessary to deviate from the amountsmentioned, in particular depending on the body weight or the type ofadministration route, on individual behaviour towards the medicament,the nature of its formulation and the point in time or interval at whichadministration takes place. Thus, in some cases it may be sufficient tomanage with less than the abovementioned minimum amount, while in othercases the upper limit mentioned must be exceeded. In the case of theadministration of larger amounts, it may be advisable to divide theseinto several individual doses over the course of the day.

PREPARATION OF THE STARTING COMPOUNDS Example I4-Bromomethyl-2-phenyl-benzothiazole ##STR20##

42.8 g (190 mmol) of 4-methyl-2-phenyl-benzothiazole [comparePerregaard, Lawesson, Acta Chem. Scand. Ser. B, 31, 203 (1977)] weredissolved in 1 l of carbon tetrachloride, and catalytic amounts of2,2'-azoisobutyronitrile were added. 40.6 g (0.228 mol) ofN-bromosuccinimide (NBS) were were added under reflux in portions andthe mixture was boiled overnight. A further 40.6 g of NBS were added andthe mixture was boiled for 2 h. After cooling, the mixture was dilutedwith methylene chloride, washed with water, dried and concentrated, andthe residue was crystallized using petroleum ether.

Yield: 53 g (92% of theory)

M.p.: 114°-115° C.

Example II 4-Acetoxymethyl-2-phenyl-benzothiazole ##STR21##

53 g (0 176 mol) of the compound from Example I and 20 g (0.2 mol) ofpotassium acetate were stirred at room temperature in 500 ml ofdimethylformamide for 24 h, the solvent was stripped off in vacuo, waterwas added, and the product was filtered off with suction and dried.

Yield: 46 g (92% of theory)

M.p.: 83°-84° C.

Example III 4-Hydroxymethyl-2-phenyl-benzothiazole ##STR22##

43 g of the compound from Example II were dissolved in 1 l of absolutemethanol, 5 g of potassium carbonate were added and after 10 minutes atroom temperature the mixture was concentrated. The residue was taken upusing methylene chloride, and the solution was washed, dried andconcentrated. 90% of theory of the title compound was obtained.

M.p.: 116°-117° C.

Example IV 2-Phenyl-benzothiazole-4-carbaldehyde ##STR23##

26.5 g (0.11 mol) of the compound from Example III were dissolved in 400ml of methylene chloride and the mixture was boiled under reflux with 50g of manganese dioxide (active) overnight. After cooling, the solid wasfiltered off with suction and the filtrate was concentrated.

Yield: 25 g (85% of theory)

M.p.: 127°-128° C.

Example V 2'-Chloro-3'-methyl-benzanilide ##STR24##

57 g (0.4 mol) of 2-chloro-3-methyl-aniline [CA 89, 30772h) weredissolved in 1.5 1 of toluene, 55 g of potassium carbonate were addedand 62 g (0.4 mol) of benzoyl chloride were added dropwise at 80° C.After reaction is complete, the solid was filtered off in the cold andwashed with water, and the filtrate was dried. After concentrating andtriturating with petroleum ether 98 g of product (100%) crystallized.

M.p.: 125°-126° C.

Example VI 2'-Chloro-3'-methyl-thiobenzanilide ##STR25##

98 g (0.4 mol) of the compound from Example V and 162 g (0.4 mol) ofLawesson's reagent were boiled in 1 l of toluene overnight, and themixture was concentrated and purified on SiO₂ (cyclohexane/ethylacetate=8:2)

Yield: 93 g (80% of theory) as a yellow oil.

Example VII 7-Methyl-2-phenyl-benzothiazole ##STR26##

91.6 g (0.35 mol) of the compound from Example VI in 1 l ofdimethylformamide were boiled under reflux with 64 g (0.42 mol) ofdiazabicycloundecane for 3 h. The mixture was concentrated, the residuewas taken up in methylene chloride/water, and the solution was renderedweakly acidic, washed with water, dried and concentrated.

Yield: 70 g (89% of theory)

M.p.: 53°-54° C.

Example VIII 7-Bromomethyl-2-phenyl-benzothiazole ##STR27##

The compound was obtained in analogy to Example I.

M.p.: 104°-105° C.

Example IX 7-Acetoxymethyl-2-phenyl-benzothiazole ##STR28##

The compound was obtained in analogy to the procedure for Example II.

M.p.: 64°-65° C.

Example X 7-Hydroxymethyl-2-phenyl-benzothiazole ##STR29##

The compound was obtained in analogy to the procedure for Example III.

M.p.: 86°-87° C.

Example XI 2-Phenyl-benzothiazole-7-carbaldehyde ##STR30##

The compound was obtained in analogy to the procedure for Example IV.

M.p. 136° C.

Example XII 4-Dibromomethyl-2-phenyl-benzoxazole ##STR31##

3.5 g (17 mmol) of 4-methyl-2-phenyl-benzoxazole [J. Org. Chem. 46, 3259(1981)] and 6 g of N-bromosuccinimide in 150 ml of carbon tetrachloridewere boiled under reflux with catalytic amounts of2,2'-azoisobutyronitrile. After 7 hours, a further 6 g ofN-bromosuccinimide and 2,2'-azoisobutyronitrile were added and themixture was boiled for a further 7h. After cooling, it was washed withwater, dried and concentrated.

Yield: 5.9 g (96% of theory)

M.p.: 106° C.

Example XIII 2-Phenylbenzoxazole-4-carbaldehyde ##STR32##

5.5 g (14.9 mmol) of the compound from Example XII were stirred at 100°C. with 30 ml of concentrated sulphuric acid for 1 h, the mixture waspoured into water, and the precipitate was filtered off with suction anddried.

Yield: 3.3 g (100% of theory)

M.p. 116° C.

Example XIV Methyl 3-benzoylamino-2-hydroxy-benzoate ##STR33##

20 mmol of methyl 3-amino-2-hydroxy-benzoate were stirred at roomtemperature in toluene with 20 mmol of benzoyl chloride for 4 hours withthe addition of dimethylaniline, the mixture was concentrated and theresidue was recrystallized from EtOH. M.p.: 105° C.

Example XV Methyl 2-benzoxazole-7-carboxylate ##STR34##

5.8 ml of CCl₄ in 5 ml of acetonitrile were added to 30 mmol of thecompound from Example XIV, 30 mmol of benzoic acid, 50 mmol oftriphenylphosphine and 120 mmol of triethylamine in 100 ml ofacetonitrile at 3° C. under argon in the course of 15 min and themixture was stirred at room temperature for 20 hours and concentrated,diethyl ether was added to the residue, the solid was filtered off withsuction, the filtrate was concentrated and the residue was separated onsilica gel. M.p.: 77° C. (white needles)

Example XVI 7-Hydroxymethyl-2-phenyl-benzoxazole ##STR35##

10 mmol of the compound from Example XV were dissolved in 50 ml oftoluene, then 40 ml of DIBAH*(20% strength in toluene) were added at 0°C. and the mixture was stirred at room temperature for 2 h. Afterworking up with sulphuric acid, the title compound was obtained.

M.p.: 131° C. (from ether)

Example XVII 2-Phenyl-benzoxazole-7-carbaldehyde ##STR36##

10 mmol of the compound from Example XVI were boiled under reflux with50 mmol of MnO₂ (active) in 50 ml of acetone for 6 h, the solid wasfiltered off with suction and the filtrate was concentrated. The residuewas recrystallized from isopropanol. M.p.: 107° C.

Example XVIII 2-(3-Pyridyl)-benzoxazole-7-carbaldehyde ##STR37##

The compound was prepared analogously to the procedures of Examples XIVto XVII.

M.p.: 140° C. (yellow needles).

PREPARATION EXAMPLES Example 1 Isopropyl3-cyano-2,6-dimethyl-4-(2-phenyl-benzothiazol-7-yl)-1,4-dihydropyridine-5-carboxylate##STR38##

10 mmol of 2-phenyl-benzothiazole-7-carboxaldehyde, 10 mmol of isopropylacetoacetate and 10 mmol of 3-aminocrotononitrile are boiled overnightin 20 ml of ethanol, the mixture is concentrated and the residue ispurified on a silica gel column (cyclohexane/ethyl acetate=6:4)

Yield: 28% of theory

M.p.: 218° C.

The compounds shown in Tables 1, 2 and 3 were prepared in analogy to theprocedure of Example 1:

                  TABLE 1                                                         ______________________________________                                         ##STR39##                                                                    Example No.  R.sup.4         M.p. (°C.)                                ______________________________________                                        2            --C.sub.2 H.sub.5                                                                             249                                              3            --CH.sub.3      240-241                                                        ##STR40##      178                                              5                                                                                           ##STR41##      amorphous                                        ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                         ##STR42##                                                                    Example No. R.sup.4      R      M.p. (°C.)                             ______________________________________                                         6          --CH.sub.3   H      218                                            7          --C.sub.2 H.sub.5                                                                          H      236                                            8          --CH(CH.sub.3).sub.2                                                                       H      198                                            9          --C.sub.2 H.sub.5                                                                          2-Cl   241                                           10          --C.sub.2 H.sub.5                                                                          3-F    222                                           11          --C.sub.2 H.sub.5                                                                          4-F    254                                           12          --C.sub.2 H.sub.5                                                                          2-F    216                                           13          --C.sub.2 H.sub.5                                                                          3-Cl   232                                           14          --C.sub.2 H.sub.5                                                                          4-Cl   212                                           ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                         ##STR43##                                                                    Example No.     R.sup.4 M.p. (°C.)                                     ______________________________________                                        15              --C.sub.2 H.sub.5                                                                     246                                                   ______________________________________                                    

Example 16 Methyl2,6-dimethyl-3-nitro-4-(2-phenyl-benzothiazol-7-yl)-1,4-dihydropyridine-5-carboxylate##STR44##

10 mmol of 2-phenyl-benzothiazole-7-carboxaldehyde, 10 mmol ofnitroacetone and 10 mmol of methyl 3-aminocrotonate are boiled in 20 mlof ethanol overnight, the mixture is concentrated and the residue ispurified on a silica gel column (cyclohexane/ethyl acetate=6:4)

Yield: 25% of yellow crystals

M.p. 233° C. (dec.)

The compounds shown in Tables 4, 5 and 6 were prepared in analogy to theprocedure of Example 16:

                  TABLE 4                                                         ______________________________________                                         ##STR45##                                                                    Example No.    R.sup.4    M.p. (°C.)                                   ______________________________________                                        17             --C.sub.2 H.sub.5                                                                        222                                                 18             --CH(CH.sub.3).sub.2                                                                     215                                                 ______________________________________                                    

                  TABLE 5                                                         ______________________________________                                         ##STR46##                                                                    Example No.   R.sup.4   R      M.p. (°C.)                              ______________________________________                                        19            --C.sub.2 H.sub.5                                                                       H      234                                            20            --C.sub.2 H.sub.5                                                                       2-Cl   196                                            21            --C.sub.2 H.sub.5                                                                       3-F    204                                            22            --C.sub.2 H.sub.5                                                                       4-F    238                                            23            --C.sub.2 H.sub.5                                                                       2-F    221                                            24            --C.sub.2 H.sub.5                                                                       3-Cl   221                                            25            --C.sub.2 H.sub.5                                                                       4-Cl   246                                            ______________________________________                                    

                  TABLE 6                                                         ______________________________________                                         ##STR47##                                                                    Example No.     R.sup.4 M.p. (°C.)                                     ______________________________________                                        26              --C.sub.2 H.sub.5                                                                     229                                                   ______________________________________                                    

Example 27 Methyl2-methyl-5-oxo-4-(2-phenyl-benzothiazol-7-yl)-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate##STR48##

10 mmol of 2-phenyl-benzothiazole-7-carboxaldehyde, 10 mmol of4-acetoxyacetoacetic ester and 10 mmol of methyl 3-aminocrotonate areboiled in 20 ml of methanol overnight, then 6 ml of dilute hydrochloricacid are added and the mixture is boiled for 30 minutes. It isconcentrated and purified on a silica gel column (cyclohexane/ethylacetate=1:1).

Yield: 30%

M.p.: 275° C.

The compounds shown in Tables 7 and 8 were prepared in analogy to theprocedure of Example 27:

                  TABLE 7                                                         ______________________________________                                         ##STR49##                                                                    Example No.    R.sup.4    M.p. (°C.)                                   ______________________________________                                        28             --C.sub.2 H.sub.5                                                                        165                                                 29             --CH(CH.sub.3).sub.2                                                                     195                                                 ______________________________________                                    

                  TABLE 8                                                         ______________________________________                                         ##STR50##                                                                    Example No. R.sup.4      R      M.p. (°C.)                             ______________________________________                                        30          --CH.sub.3   H      285                                           31          --C.sub.2 H.sub.5                                                                          H      249                                           32          --CH(CH.sub.3).sub.2                                                                       H      210                                           33          --C.sub.2 H.sub.5                                                                          2-Cl   168                                           34          --C.sub.2 H.sub.5                                                                          3-F    267                                           35          --C.sub.2 H.sub.5                                                                          4-F    199                                           36          --C.sub.2 H.sub.5                                                                          2-F    196                                           37          --C.sub.2 H.sub.5                                                                          3-Cl   234                                           38          --C.sub.2 H.sub.5                                                                          4-Cl   198                                           ______________________________________                                    

The compounds shown in Table 9 were prepared in analogy to the procedureof Example 1.

                  TABLE 9                                                         ______________________________________                                         ##STR51##                                                                    Example No.    R.sup.4    M.p. (°C.)                                   ______________________________________                                        39             --CH(CH.sub.3).sub.2                                                                     191                                                 40             --CH.sub.3 199                                                 ______________________________________                                    

The compounds shown in Table 10 were prepared in analogy to theprocedure of Example 16.

                  TABLE 10                                                        ______________________________________                                         ##STR52##                                                                    Example No.     R.sup.4 M.p. (°C.)                                     ______________________________________                                        41              --C.sub.2 H.sub.5                                                                     246                                                   42              --CH.sub.3                                                                            245                                                   ______________________________________                                    

The compounds shown in Table 11 were prepared in analogy to theprocedure of Example 17.

                  TABLE 10                                                        ______________________________________                                         ##STR53##                                                                    Example No.     R.sup.4 M.p. (°C.)                                     ______________________________________                                        43              --C.sub.2 H.sub.5                                                                     160                                                   ______________________________________                                    

It will be understood that the specificatin and examples areillustrative but not limitative of the present invention and that otherembodimetns within the spirit and scope of the invention will suggestthemselves to those skilled in the art.

We claim:
 1. A 4-hetero-substituted-1,4-dihydropyridine of the formula##STR54## in which R¹ and R⁵ are identical or different and representstraight-chain or branched alkyl having up to 8 carbon atoms,R²represents nitro or cyano, R³ represents a radical of the formula##STR55## in which R⁶ denotes hydrogen, halogen or straight-chain orbranched alkyl or alkoxy in each case having up to 8 carbon atoms,R⁷denotes aryl having 6 to 10 carbon atoms, which is optionallymonosubstituted or disubstituted by identical or different substituentsfrom the group consisting of halogen, nitro, cyano, trifluoromethyl,trifluoromethoxy, trifluoromethylthio, straight-chain or branched alkyl,alkoxy or alkoxycarbonyl in each case having up to 8 carbon atoms, andcarboxyl, or denotes thienyl or pyridyl, R⁴ represents hydrogen, orrepresents straight-chain or branched alkyl, alkenyl, alkadienyl oralkynyl in each case having up to 10 carbon atoms which are optionallymonosubstituted or disubstituted by identical or different substituentsfrom the group consisting of halogen, hydroxyl, carboxyl, cyano, nitro,phenoxy and straight-chain or branched alkylthio, alkoxy,alkoxycarbonyl, acyl or acyloxy in each case having up to 8 carbonatoms, and phenoxy or phenyl optionally monosubstituted or disubstitutedby identical or different substituents from the group consisting ofhalogen and straight-chain or branched alkyl or alkoxy in each casehaving up to 6 carbon atoms,or a physiologically acceptable saltthereof.
 2. A compound or salt thereof according to claim 1, in whichR¹and R⁵ are identical or different and represent straight-chain orbranched alkyl having up to 6 carbon atoms, R² represents nitro orcyano, R³ represents a radical of the formula ##STR56## in which R⁶denotes hydrogen, fluorine, chlorine or straight-chain or branched alkylor alkoxy in each case having up to 2 carbon atoms,R⁷ denotes phenylwhich is optionally substituted by fluorine, chlorine, nitro, cyano,trifluoromethyl or by straight-chain or branched alkyl or alkoxy in eachcase having up to 6 carbon atoms, or denotes pyridyl or thienyl, R⁴represents hydrogen or represents straight-chain or branched alkyl oralkenyl in each case having up to 8 carbon atoms which are optionallysubstituted by fluorine, chlorine, hydroxyl, carboxyl, cyano, nitro orby straight-chain or branched alkylthio, alkoxy, alkoxycarbonyl, acyl oracyloxy in each case having up to 6 carbon atoms or by phenoxy orphenyl.
 3. A compound or salt thereof according to claim 1 in whichR¹and R⁵ are identical or different and represent straight-chain orbranched alkyl having up to 4 carbon atoms, R² represents nitro orcyano, R³ represents a radical of the formula ##STR57## in which R⁶denotes hydrogen, chlorine or methyl,R⁷ denotes phenyl which isoptionally substituted by fluorine, chlorine, nitro, trifluoromethyl orby straight-chain or branched alkyl, acyl or alkoxy in each case havingup to 4 carbon atoms, or denotes pyridyl, R⁴ represents hydrogen, orrepresents straight-chain or branched alkyl having up to 6 carbon atoms,which is optionally substituted by hydroxyl, carboxyl, cyano or bystraight-chain or branched alkoxycarbonyl, alkoxy or acyloxy in eachcase having up to 4 carbon atoms.
 4. A compound according to claim 1,wherein such compound is ethyl3-cyano-2,6-dimethyl-4-(2-phenylbenzothiazol-4-yl)-1,4-dihydropyridine-5-carboxylateof the formula ##STR58## or a physiologically acceptable salt thereof.5. A compound according to claim 1, wherein such compound is isopropyl3-cyano-2,6-dimethyl-4-(2-phenyl-benzothiazol-4-yl)-1,4-dihydropyridine-5-carboxylateof the formula ##STR59## or a physiologically acceptable salt thereof.6. A compound according to claim 1, wherein such compound is ethyl3-cyano-2,6-dimethyl-4-[2-(3-fluorophenyl)-benzothiazol-4-yl]-1,4-dihydropyridine-5-carboxylateof the formula ##STR60## or a physiologically acceptable salt thereof.7. A compound according to claim 1, wherein such compound is ethyl3-cyano-2,6-dimethyl-4-[2-(4-fluorophenyl)-benzothiazol-4-yl]-1,4-dihydropyridine-5-carboxylateof the formula ##STR61## or a physiologically acceptable salt thereof.8. A compound according to claim wherein such compound is ethyl3-cyano-2,6-dimethyl-4-[2-(2-fluorophenyl)-benzothiazol-7-yl]-1,4-dihydropyridine-5-carboxylateof the formula ##STR62## or a physiologically acceptable salt thereof.9. A composition exhibiting positive inotropic action comprising anamount effective therefore of a compound or salt according to claim 1and a physiologically acceptable diluent.
 10. In the method of treatinga patient for coronary vessel disorders by administration of aneffective amount of a compound which exhibits positive inotropicactivity, the improvement wherein said compound is a compound or saltthereof according to claim
 1. 11. The method according to claim 10,wherein such compound isethyl3-cyano-2,6-dimethyl-4-(2-phenyl-benzothiazol-4-yl)-1,4-dihydropyridine-5-carboxylate,isopropyl3-cyano-2,6-dimethyl-4-(2-phenylbenzothiazol-4-yl)-1,4-dihydropyridine-5-carboxylate,ethyl3-cyano-2,6-dimethyl-4-[2-(3-fluorophenyl)-benzothiazol-4yl]-1,4-dihydropyridine-5-carboxylate,ethyl3-cyano-2,6-dimethyl-4-[2-(4-fluorophenyl)-benzothiazol-4-yl]-1,4-dihydropyridine-5-carboxylateor ethyl3-cyano-2,6-dimethyl-4-[2-(2-fluorophenyl)-benzothiazol-4-yl]-1,4-dihydropyridine-5-carboxylate,ora physiologically acceptable salt thereof.